Despite advances in therapies over the past 3 decades, up to 30% of RA patients continue to live with uncontrolled disease even with frequent switching of DMARD and biological therapies suggesting that RA is a heterogeneous disease that may evolve over a lifetime. The cellular and molecular mechanisms that underlie the heterogeneity of RA are largely unknown. A detailed understanding of the pathways responsible for the differential responses of RA patients to treatment would be invaluable to facilitate the optimization of treatment regimens for individual RA patients and allow the implementation of effective `treat-to-target approaches. This proposal will take advantage of unique cohorts of RA patients and a well-integrated multidisciplinary team of clinicians and scientists at the Hospital for Special Surgery (HSS), the New York Genome Center (NYGC) and Mount Sinai Hospital (MSH) at the University of Toronto to gain a broad understanding of the molecular pathways that control the function of these distinct cellular compartments in different clinical settings. Or major goals are to: a) utilize the unparalleled access of HSS physicians to over 26,000 surgical cases/year to obtain paired samples of peripheral blood and synovial tissues from RA and control patients undergoing surgical procedures to perform detailed cellular, molecular, and histological analyses aimed at uncovering molecular pathways whose deregulation is shared between peripheral blood samples and tissue specimens, b) exploit the phenomenon of disease worsening or flare in patients discontinuing DMARDs and biologics during the perioperative period, to perform longitudinal studies to unmask pathways that distinguish flaring vs. non-flaring patients, and c) extend the results obtained from these initial studies to cohorts of early RA patients observed longitudinally who are DMARD and/or TNF responders versus non-responders.